AAV-Mediated Gene Transfer Restores a Normal Muscle Transcriptome in a Canine Model of X-Linked Myotubular Myopathy

Mol Ther. 2020 Feb 5;28(2):382-393. doi: 10.1016/j.ymthe.2019.10.018. Epub 2019 Nov 11.


Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Our previous work on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrected structural abnormalities within the muscle and restored contractile function, with affected dogs surviving more than 4 years post injection. This remarkable therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology and to what extent the whole muscle transcriptome is restored to normal after gene transfer. Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously described canine cohort that showed dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice but also identified transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created metrics to pinpoint potential biomarkers of disease progression and correction.

Keywords: AAV; XLMTM; biomarkers; gene therapy; myotubularin; transcriptome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Dogs
  • Gene Dosage
  • Gene Expression Profiling
  • Gene Transfer Techniques*
  • Genetic Therapy*
  • Genetic Vectors / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Muscle, Skeletal / metabolism*
  • Myopathies, Structural, Congenital / genetics*
  • Transcriptome*
  • Transduction, Genetic


  • Biomarkers